FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
AN IMPROVED PROCESS FOR THE PREPARATION OF NICARDIPINE OR SALT THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides an improved process for the preparation of nicardipine or salt thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.
1

4. DESCRIPTION
The present invention provides an improved process for the preparation of nicardipine or salt thereof.
Nicardipine hydrochloride of formula I is chemically known as 2-(benzyl-methyl amino) ethylmethyl-1, 4-dihydro - 2, 6-dimethyl-4-(m-nitrophenyl)- 3, 5-pyridine dicarboxylate monohydrochloride. Nicardipine hydrochloride is indicated for the management of patients with chronic stable angina (effort-associated angina) and for the treatment of hypertension.

Formula I
U.S. patent No. 3,985,758 disclosed the process of preparation of nicardipine and salt thereof wherein the process involves reaction of 3-methoxycarbonyl-2,6-dimethyl-4-(m-nitro phenyl)-1,4-dihydropyridine-5-carboxylic acid with N-(2-hydroxyethyl)-N-benzyl-methylamine and N,N'-dicyclohexylcarbodiimide to get nicardipine which is then converted to its hydrochloride salt form.
U.S. patent No. 4,769,465 and european patent No. 202625 provides the process for the preparation of nicardipine hydrochloride involving partial hydrolysis of dimethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and the reaction of the obtained 3-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid either with N-(2-hydroxyethyl)-N-benzyl-methylamine or with N-(2-haloethyl)-N-benzyl-methylamine which then converted to its hydrochloride salt.
U.S. patent No. 4,705,797 disclosed the diester of 1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid or the stereoisomers or pharmaceutically acceptable
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acid addition salts thereof prepared from the aromatic aldehydes and esters of acetoacetic and 3-aminocrotonic acids.
In J. Am. Chem. Soc. 76, 4920-23, 1954, disclosed the process of preparation of N-(2-chloroethyl)-N-benzyl-methylamine, an useful intermediate in the synthesis of nicardipine or salt thereof.
Several other processes are known in the art for preparation of nicardipine and related compounds or salts thereof such as in U.S. patent Nos. 4,673,564, 5,310,917, 5,245,039, 4,600,778 and european patent application Nos. 445987 A3, 245680 A3, 1682101 A2.
Present inventors while working on the process for preparation of nicardipine or salt thereof have surprisingly found that when 3-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid (hereafter referred as carboxylic acid intermediate) was reacted with N-(2-hydroxyethyl)-N-benzyl-methylamine (hereafter referred as amine intermediate) and N,N'-dicyclohexylcarbodiimide (DCC) in presence of proton acceptor, the nicardipine or salt thereof was obtained in high yield. The inventors further noted that, in presence of proton acceptor, only one mole of amine intermediate was required for the reaction of one mole of carboxylic acid intermediate instead of excess addition of amine intermediate when the reaction was carried out in absence of proton acceptor. The process of present invention is easily scalable at industrial scale.
In the aspect of the present invention there is provided a process for the preparation of nicardipine or salt thereof. The process includes step of:
a) reacting 3-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydro pyridine -5-carboxylic acid with N-(2-hydroxyethyl)-N-benzyl-methylamine in presence of proton acceptor,
b) isolating nicardipine or salt thereof from the reaction mass thereof.
3

The process of present invention involves reacting 3-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydro pyridine -5-carboxylic acid (0.1 mole) with N-(2-hydroxyethyl)-N-benzyl-methylamine (0.1 mole) and N,N'-dicyclohexyl carbodiimide (DCC) in presence of catalytic amount proton acceptor such as pyridine, dimethyl amino pyridine (DMAP), tributyl amine, dimethyl amine or the like, in an organic solvent. The organic solvent includes ethyl acetate, ethanol, tetrahydrofuran, chloroform, dichloromethane, toluene and the like. The reaction mixture was then heated to reflux. After completion of reaction, the reaction mixture was cooled and filtered. The filtered dicyclohexyl urea was washed with organic solvent. The combined organic layer was then washed with aqueous hydrochloric acid and the title compound nicardipine hydrochloride was isolated from the reaction mass thereof.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE Preparation of nicardipine hydrochloride
A mixture of 5-Methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (15 gm), dicyclohexylcarbodiimide (11.2 gm), N-Benzyl-N-Methyl ethanol amine (8.3 gm), dimethylamino pyridine (0.6 gm) in ethyl acetate (0.22 litre) was refluxed for 3 hours. The reaction mixture was then cooled to room temperature and filtered. Filtered Dicyclohexyl urea was washed with ethylacetate (30 ml) and combined organic layer washed successively with sodium chloride solution and 10% Sodium Carbonate solution (0.1 litre). Organic layer was then extracted with 10% hydrochloric acid solution (0.1 litre) and nicardipine hydrochloride was isolated from the reaction mass thereof.
Yield : 20.1 gm.
HPLC purity: 99.3%
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WE CLAIM:
1. A process for the preparation of nicardipine or salt thereof. The process
comprising:
a) reacting 3-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydro pyridine -5-carboxylic acid with N-(2-hydroxyethyl)-N-benzyl-methylamine in presence of proton acceptor,
b) isolating nicardipine or salt thereof from the reaction mass thereof.

2. A process of claim 1, wherein the process further comprises of dicyclohexyl carbodiimide (DCC).
3. A process of claim 1, wherein the proton acceptor is base such as pyridine, dimethyl amino pyridine (DMAP), tributyl amine, dimethyl amine or the like.
4. A process of claim 1, wherein the reaction is carried out in presence or absence of organic solvent.
5. A process of claim 4, wherein the organic solvent includes ethyl acetate, ethanol, tetrahydrofuran, chloroform, dichloromethane, toluene and the like.
6. Nicardipine hydrochloride having the purity 99.0 % or more.